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Artículo

The p.Cys1281Tyr variant in the hinge module/flap region of thyroglobulin causes intracellular transport disorder and congenital hypothyroidism

Gomes Pio, MauricioIcon ; Adrover, EzequielaIcon ; Miras, Mirta Beatriz; Sobrero, Gabriela Maria; Molina, Maricel FernandaIcon ; Scheps, KarenIcon ; Rivolta, Carina MarcelaIcon ; Targovnik, Hector ManuelIcon
Fecha de publicación: 09/07/2023
Editorial: Elsevier Ireland
Revista: Molecular and Cellular Endocrinology
ISSN: 0303-7207
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Genética Humana

Resumen

Congenital hypothyroidism (CH) due to thyroglobulin (TG) variants causes very low serum TG levels with normal or enlarged thyroid glands, depending on the severity of the defect, and with autosomal recessive inheritance. The purpose of this study was to functionally characterize p.Cys1281Tyr variant in the TG gene in order to increase our knowledge of the molecular mechanisms associated with CH. In order to find evidence that support the hypothesis that the p.Cys1281Tyr variant would affect the TG folding were performed amino acid prediction, 3D modeling and transient expression analysis in HEK293T cells. 18 of the 21′′in silico” algorithms predict a deleterious effect of the p.Cys1281Tyr variant. The full-length 3D model p.Cys1281Tyr TG showed disulfide bond cleavage between the cysteines at positions 1249 and 1281 and rearrangement of the TG structure, while transient expression analysis indicated that p.Cys1281Tyr causes retention of the protein inside the cell. Consequently, these results show that this pathogenic variant makes it impossible for TG to fulfill its function in the biosynthesis process of thyroid hormones, causing CH. In conclusion, our results confirm the pathophysio logical importance of misfolding of TG as a consequence of p.Cys1281Tyr variant located in the hinge module/ flap region of TG.
Palabras clave: Congenital hypothyroidism , Hinge module/flap region , Intracellular retention
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/249431
URL: https://linkinghub.elsevier.com/retrieve/pii/S0303720723000990
DOI: http://dx.doi.org/10.1016/j.mce.2023.111948
Colecciones
Articulos(INIGEM)
Articulos de INSTITUTO DE INMUNOLOGIA, GENETICA Y METABOLISMO
Articulos(OCA HOUSSAY)
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA HOUSSAY
Citación
Gomes Pio, Mauricio; Adrover, Ezequiela; Miras, Mirta Beatriz; Sobrero, Gabriela Maria; Molina, Maricel Fernanda; et al.; The p.Cys1281Tyr variant in the hinge module/flap region of thyroglobulin causes intracellular transport disorder and congenital hypothyroidism; Elsevier Ireland; Molecular and Cellular Endocrinology; 572; 9-7-2023; 1-7
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